Medicinal Products

APTIVUS 250 mg

Generic drug of the therapeutic class: Infectiology - Parasitology
Active ingredients: Tipranavir
laboratory: Boehringer Ingelheim Int

Soft capsule
Box of 1 bottle of 120
All forms

Indication

APTIVUS, co-administered with low dose ritonavir, is indicated for the treatment of HIV-1 infection in combination with other antiretroviral agents in heavily pre-treated adults and adolescents aged 12 years and older having multi-resistant viruses to protease inhibitors. APTIVUS should only be used as part of a combination of antiretroviral therapy in patients who have no other therapeutic alternatives.

This indication is based on the results of two Phase III trials conducted in heavily pretreated adult patients (previously median-12 antiretroviral) with protease inhibitor-resistant viruses and the results of a phase 2 trial. II evaluating the pharmacokinetics, safety and efficacy of APTIVUS in the most frequently pretreated adolescent patients aged 12 to 18 years (see section 5.1 ).

When initiating APTIVUS, co-administered with low-dose ritonavir, each patient's treatment history and analysis of mutant patterns associated with different antiretrovirals should be carefully evaluated. Genotypic and phenotypic resistance tests (where available) and therapeutic history should guide the use of APTIVUS. When initiating therapy, combinations of mutations that may have a negative impact on virologic response to APTIVUS therapy, co-administered with low dose ritonavir, should be considered (see section 5.1 ).

Dosage APTIVUS 250 mg Soft Capsule Box of 1 Bottle of 120

APTIVUS should always be administered with low dose ritonavir as a pharmacokinetic booster and in combination with other antiretroviral drugs. The Summary of Product Characteristics of ritonavir should therefore be consulted prior to initiation of APTIVUS therapy (particularly with respect to contraindications, warnings and adverse reactions).

APTIVUS should be prescribed by physicians experienced in the management of HIV-1 infection.

APTIVUS with ritonavir should not be used in patients who are naive to antiretroviral therapy.

Dosage

Patients should be informed of the need to take APTIVUS and ritonavir daily according to the prescription. If a dose has been missed for more than 5 hours in relation to the scheduled time, the patient should wait and then take the next dose of APTIVUS and ritonavir at the usual time of day.

If a dose has been missed for less than 5 hours from the scheduled time, the patient should take the missed dose immediately and then take the next dose of APTIVUS and ritonavir at the usual time of day.

adults

The recommended dose of tipranavir is 500 mg co-administered with 200 mg ritonavir (low dose ritonavir) twice daily.

Ritonavir doses less than 200 mg twice daily should not be used due to the risk of altering the efficacy profile of the combination.

Pediatric population

Teenagers from 12 years old

The recommended dose of APTIVUS is 500 mg co-administered with 200 mg ritonavir (low dose ritonavir) twice daily (see Warnings and Precautions for Precautionary Measures in Adolescents). .

Ritonavir doses less than 200 mg twice daily should not be used due to the risk of altering the efficacy profile of the combination.

Given the limited efficacy and safety data currently available in adolescents (see section 5.1 ), close monitoring of virologic response and tolerance is particularly necessary in this group of patients.

Children under 12 years

The safety and efficacy of APTIVUS capsules in children aged 2 to 12 years have not been established. Currently available data are described under Pharmacodynamic properties and Pharmacokinetic properties, but no dosage recommendation can be given.

In addition, appropriate dose adjustment in children under 12 years of age can not be performed with APTIVUS capsules. APTIVUS oral solution is available for children aged 2 to 12 years (please refer to the corresponding SPC for details).

The safety and efficacy of APTIVUS in children under 2 years of age have not been established. No data available.

Elderly patients

Clinical studies with APTIVUS did not include a sufficient number of subjects aged 65 and over to determine whether they responded differently from younger subjects (see section 5.2 ).

In general, caution should be exercised when administering and monitoring APTIVUS in elderly patients, in whom decreased hepatic, renal or cardiac function, concomitant disease or associated therapy is more common ( see section Warnings and precautions for use ).

Hepatic insufficiency

Tipranavir is metabolized by the liver. Hepatic impairment may result in increased exposure to tipranavir and a worsening of its safety profile. Therefore, APTIVUS should be used with caution, and with increased monitoring, in patients with mild hepatic impairment (Child-Pugh Class A). APTIVUS is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh Class B or C) (see sections Contraindications, Warnings and Precautions, and Pharmacokinetic Properties ).

Renal failure

No dose adjustment is necessary in patients with renal impairment (see Warnings and Precautions and Pharmacokinetic Properties sections).

Administration mode

APTIVUS Soft Capsules, co-administered with low dose ritonavir, should be administered in the presence of food (see section 5.2 ).

Against indications

Hypersensitivity to the active substance or to any of the excipients.

Patients with moderate or severe hepatic impairment (Child-Pugh Class B or C).

Concomitant use of rifampicin and APTIVUS with low dose ritonavir is contraindicated (see section 4.5 ).

Herbal preparations containing St. John's wort ( Hypericum perforatum ) should not be used during treatment with APTIVUS as they may reduce plasma concentrations and clinical efficacy of tipranavir (see section 4.5). interactions ).

Co-administration of APTIVUS, with low-dose ritonavir, and active substances whose clearance is highly dependent on CYP3A, for which an increase in plasma concentrations may lead to serious and / or potentially prognostic adverse effects vital, is contraindicated. These active substances include antiarrhythmics (amiodarone, bepridil, quinidine), antihistamines (astemizole, terfenadine), rye ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine), stimulants of gastrointestinal motility (cisapride), neuroleptics (pimozide, sertindole), sedatives / hypnotics (oral midazolam and triazolam, for precautions in parenteral administration of midazolam see section Interactions with other medicinal products and other forms of interaction ) and inhibitors of HMG-CoA reductase (simvastatin and lovastatin). In addition, the co-administration of APTIVUS with low-dose ritonavir, and drugs whose clearance is highly dependent on CYP2D6, such as some antiarrhythmics (flecainide, propafenone, and metoprolol used in heart failure), are counter-controlled. indicated (see section Interactions with other medicinal products and other forms of interaction ).

Aptivus side effects

APTIVUS, co-administered with low dose ritonavir, has been associated with significant hepatic toxicity. In the RESIST Phase III clinical trials, the frequency of transaminase elevations was significantly increased in the ritonavir-associated tipranavir arm relative to the comparator arm. Careful monitoring is therefore required in patients treated with APTIVUS, co-administered with low dose ritonavir (see Warnings and Precautions ).

Currently available data on the use of APTIVUS, co-administered with low dose ritonavir, in patients co-infected with hepatitis B or C are limited. APTIVUS should be used with caution in patients co-infected with hepatitis B or C. APTIVUS should only be used in this patient population if the expected benefit outweighs the potential risk and if clinical and laboratory monitoring is increased. .

adults

Tipranavir (soft capsules), co-administered with low dose ritonavir, was evaluated in combination with other antiretrovirals in a total of 6, 308 adult HIV-infected patients in clinical studies, including compassionate studies. Of these patients, 5, 219 received the 500 mg / 200 mg dose twice daily. In clinical trials, 909 adults, including 541 in the pivotal phase 3 trials RESIST-1 and RESIST-2, were treated with the 500 mg / 200 mg dose twice daily for at least 48 weeks.

Clinically significant adverse events of any grade (Grade 1-4) observed in adult patients receiving 500 mg tipranavir with 200 mg ritonavir twice daily (n = 1397) during all Phase II and III clinical trials are listed below by organ class and frequency according to the following categories:

Very common (≥1 / 10), common (≥1 / 100 to <1/10), uncommon (≥1 / 1000 to <1/100), rare (≥ 1/10 000 to <1/1000) )

Hematological and lymphatic system disorders:

Uncommon: neutropenia, anemia, thrombocytopenia.

Immune system disorders:

Uncommon: hypersensitivity reaction

Metabolism and nutrition disorders:

Frequent: hypertriglyceridemia, hyperlipidemia

Uncommon: anorexia, decreased appetite, weight loss, hyperamylasemia, hypercholesterolemia, diabetes, hyperglycaemia

Rare: dehydration, slimming of the face,

Psychiatric disorders:

Uncommon: insomnia, sleep disorders

Nervous system disorders:

Common: headache

Uncommon: intracranial hemorrhage *, dizziness, peripheral neuropathy, somnolence

Respiratory, thoracic and mediastinal disorders:

Uncommon: dyspnoea

Gastrointestinal disorders:

Very common: diarrhea, nausea

Common: vomiting, flatulence, abdominal pain, abdominal distension, loose stools, dyspepsia.

Uncommon: gastroesophageal reflux, pancreatitis

Rare: increased lipase

Hepatobiliary disorders:

Uncommon: hepatic enzyme elevation (ALT, ASAT), cytolytic hepatitis, abnormal liver function test (ALT, ASAT), toxic hepatitis

Rare: liver failure (including fatal outcome), hepatitis, hepatic steatosis hyperbilirubinemia.

Skin and subcutaneous tissue disorders:

Frequent: rash

Uncommon: pruritus, lipohypertrophy, exanthema, lipoatrophy, acquired lipodystrophy

Musculoskeletal and systemic disorders:

Uncommon: myalgia, muscle cramp

Affection of the kidney and urinary tract:

Uncommon: renal failure

General disorders and administration site defects:

Frequency: tiredness

Uncommon: pyrexia, flu-like syndrome, malaise

* This adverse event has not been reported as an adverse event possibly related to treatment in the respective studies. The frequency estimate is based on the upper limit of the 95% confidence interval, calculated from all treated patients, in accordance with the European recommendation for SPC (3/1397, corresponds to the category "few frequent").

Description of some adverse effects

The following elements of clinical tolerance (hepatotoxicity, hyperlipidemia, bleeding, rash) were observed at a higher frequency in patients treated with ritonavir-treated tipranavir compared to patients treated in the comparator arm in RESIST clinical trials, or have been observed during the administration of tipranavir with ritonavir. The clinical significance of these observations has not yet been fully explored.

Hepatotoxicity: After 48 weeks of follow-up, the incidence of ALT and / or ASAT grade 3 or 4 abnormalities was higher in patients treated with ritonavir-treated tipranavir compared to patients treated in the comparator arm ( 10% and 3.4%, respectively). Multivariate analyzes showed that baseline ALT or ASAT above DAIDS Grade 1 and co-infection with hepatitis B or C were risk factors for these elevations. Most patients were able to continue treatment with tipranavir with ritonavir.

Hyperlipidemia: Grade 3 or 4 triglyceride elevations occurred more frequently in the tipranavir arm of ritonavir compared to the comparator arm. At 48 weeks, these rates were 25.2% in patients treated with ritonavir-treated tipranavir and 15.6% in the comparator arm.

Bleeding: A tendency for increased risk of bleeding has been observed in RESIST patients receiving tipranavir with ritonavir; the relative risk at 24 weeks was 1.98 (95% CI = 1.03, 3.80). At 48 weeks, the relative risk decreased to 1.27 (95% CI = 0.76, 2.12). There was no evidence of haemorrhagic events and no difference in coagulation parameters between treatment groups. Further evaluation is underway on the relevance of these data.

Fatal and nonfatal intracranial haemorrhage (HIC) has been reported in patients receiving tipranavir; many of these patients had medical histories or were receiving concurrently other treatments that may be causing or contributing to the HIC. However, in some cases, the role of tipranavir can not be ruled out. No hematologic abnormalities or coagulation parameters have been observed in patients treated with APTIVUS or prior to HIC. Therefore, routine monitoring of coagulation parameters is not currently indicated in APTIVUS patients.

An increased risk of HIC has already been observed in patients with advanced HIV-1 / AIDS infection, patients comparable to those treated with APTIVUS in these clinical trials.

Rash: An interaction study between tipranavir, co-administered with low dose ritonavir, and ethinyl estradiol / norethindrone conducted in women, showed a high frequency of non-serious rash. In RESIST clinical trials, the risk of rash was similar between ritonavir and comparator-treated tipranavir arms (16.3% versus 12.5%, respectively, see Warnings and Precautions ). No cases of Stevens-Johnson syndrome or Lyell syndrome have been reported in the tipranavir clinical development program.

Biological abnormalities

Frequencies of clinically pronounced (Grade 3 or 4) laboratory abnormalities reported in at least 2% of patients in ritonavir-treated tipranavir arms in Phase III (RESIST-1 and RESIST-2) clinical trials after 48 weeks corresponded to an increase in ASAT (6.1%), ALT (9.7%), amylase (6.0%), cholesterol (4.2%) and triglycerides (24.9%)., and a decrease in the number of white blood cells (5.7%).

Combination antiretroviral therapy, such as protease inhibitor-containing therapies, is associated in some patients with redistribution of body fat, including loss of peripheral subcutaneous adipose tissue, increased intra-fat mass abdominal, breast hypertrophy, and retro-cervical fat accumulation (buffalo hump). Protease inhibitors are also associated with metabolic abnormalities such as hypertriglyceridemia, hypercholesterolemia, insulin resistance and hyperglycemia.

Increases in CPK, myalgia, myositis and, rarely, rhabdomyolysis have been reported with protease inhibitors, particularly when combined with nucleoside reverse transcriptase inhibitors.

In HIV-infected patients with severe immune deficiency at the time of initiation of antiretroviral combination therapy, an inflammatory reaction to asymptomatic or residual opportunistic infections may occur (see Warnings and Precautions section). ). Reactivation of herpes and shingles viruses was observed during the RESIST trials.

Cases of osteonecrosis have been reported, particularly in patients with known risk factors, advanced HIV-related disease, or combination therapy with long-term antiretrovirals. Their frequency of occurrence is not known (see section Warnings and Precautions ).

Pediatric population

In an open label clinical trial of tipranavir plus ritonavir (Study 1182.14), 28 children aged 12 years and older received APTIVUS capsules. In general, adverse effects were similar to those seen in adults, with the exception of vomiting, rash, and pyrexia, which were reported more frequently in children than in adults. The most common moderate or severe adverse events reported during the 48-week analysis are presented below.

Moderate or severe adverse events reported most frequently in pediatric patients aged 12 to 18 years who received APTIVUS capsules (reported in at least 2 children, study 1182.14, 48-week analyzes, Full Analysis Set)

Total number of patients treated (N)

28

Events [N (%)]

Vomiting / retching

3 (10.7)

nausea

2 (7.1)

Abdominal pain 1

2 (7.1)

Rash 2

3 (10.7)

Insomnia

2 (7.1)

Increase in ALT

4 (14, 3)

1. Includes abdominal pain (N = 1) and dyspepsia (N = 1).

2. The term rash includes one or more of the following preferred terms: rash, drug rash, macular rash, papular rash, erythema, maculopapular rash, itchy rash and urticaria.

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